Genetic variants affecting COVID-19 susceptibility identified

Our genomes can influence the susceptibility and response to SARS-CoV-2 infection, determining the severity of symptoms.

Researchers collaborating as part of the COVID-19 Host Genetics Initiative are investigating the role of human genetics in determining COVID-19 susceptibility, severity and outcome. They have identified 13 genome-wide loci associated with severe manifestations of the disease. The findings, published in Nature, can be used to identify high-risk individuals and potential therapeutic targets.

'There is still substantial room for improvement in COVID-19 treatment, which can be informed by genetic analysis' said Dr Benjamin Neale, co-director of the programme in medical and population genetics at the Broad Institute at the Massachusetts Institute of Technology, and co-senior author of the study. 'Improving treatment approaches could help shift the pandemic to an endemic disease that is more localised and present at low but consistent levels in the population.'

The initiative combined genetic data from 49,562 infected individuals and two million controls, sampled from 46 studies across 19 countries. Using a large and diverse dataset enabled the researchers to produce statistically robust results quickly. The authors compared the difference in the frequencies of genetic variants between the infected and control individuals from each study, then combined the differences from each study to increase the statistical power of the data.

They identified four loci associated with increased susceptibility to COVID-19 infection and nine associated with increased disease severity. Both TYK2 and DPP9 have reported associations with increased severity of COVID-19 illness, with previous studies showing the association of these genes with increased susceptibility to autoimmune disease and lung cancer respectively (see BioNews 1076).

Two of the loci were not identified as significant until four studies of East Asian ancestry individuals were included. One locus, near to FOXP4, exhibited 32 percent frequency in East Asian ancestries, compared to two-three percent in Europeans. Eighty percent of study participants were of European ancestry, and greater global representation in datasets could help with detection of genetic variants that make people more susceptible to COVID-19.

Co-founder of the initiative, Dr Mark Daly, from the Institute for Molecular Medicine, Finland and the Broad Institute, noted 'We've been much more successful than past efforts in sampling genetic diversity because we've made a concerted effort to reach out to populations around the world. I think we still have a long way to go, but we're making very good progress.'

The initiative intends to publish ancestry-specific results once each study's sample size allows for statistically robust meta-analysis. The work conducted will facilitate a better understanding of the biological and clinical implications of host genetic factors influencing COVID-19 susceptibility and severity.